Herpes Simplex Virus Type 2 (HSV-2) is a common infection that causes a spectrum of clinical disease from mild mucocutaneous, anogenital ulcers to life-threatening conditions. Prevention of HSV-2 infection is difficult and current therapy for HSV-2 is not completely effective. Immunocompromised persons such as those with HIV are particularly vulnerable to HSV-2, manifesting more severe disease and developing higher rates of resistance to therapy. For these reasons, new, more effective therapeutic agents are needed to prevent and treat HSV-2 infection and disease, respectively, especially in persons with HIV. Recent clinical and in vitro data suggest that agents, developed for the treatment of HIV, may also have activity against HSV-2. Most compelling are data suggesting that a Tenofovir Disoproxil Fumarate (TDF)-based, vaginal microbicide reduces HSV-2 acquisition. As an extension of this finding and based on our preliminary research, I hypothesize that TDF will have direct activity against HSV-2 in vitro and that orally delivered TDF, as a component of HIV therapy, will have activity against HSV-2 in vivo. To test this hypothesis, I propose the following independent but inter-related aims. Aim 1: Investigate the potential inhibitory role of TDF on HSV-2 replication in vitro. Aim 2: Determine the potential suppressive effect of systemically delivered TDF on HSV-2 infection and its suppressive effect on subclinical HSV-2 viral shedding in vivo. Using bidirectional and translational techniques as outlined in this proposal, I will establish a fundamental understanding of TDF's action on HSV-2 while providing information about clinical relevance. Of equal importance, this career development award and the research aims as outlined above are designed to provide me with additional training in virology, clinical study design, methodology, and statistical analysis to meet my specific educational needs. The opportunities created by this career development award will culminate in the creation of a translational scientist with the skills necessary to adeptly, ethically, and accurately answer important scientific questions related to HSV-2 prevention and treatment. It will also help me to successfully obtain future independent funding, and most importantly, improve patient care. Public Health Relevance: Infection with Herpes Simplex Virus Type 2 in immunocompromised populations, such as patients with HIV, is of particular concern because it can cause severe disease and harbor resistance to drug treatment in this population. There is need to identify new agents that effectively prevent and treat HSV-2, especially in HIV infected populations. In this grant, I will investigate Tenofovir's (TDF) anti-HSV-2 activity in vivo and in vitro.